Ultrasound in Med. & Biol., Vol. 39, No. 8, pp. 1429–1439, 2013Copyright � 2013 World Federation for Ultrasound in Medicine & Biology

Printed in the USA. All rights reserved0301-5629/$ - see front matter

/j.ultrasmedbio.2013.03.007

http://dx.doi.org/10.1016

d Original Contribution

DESIGN AND EVALUATION OFAWEARABLE SELF-APPLIED THERAPEUTICULTRASOUND DEVICE FOR CHRONIC MYOFASCIAL PAIN

GEORGE K. LEWIS JR.,* MATTHEW D. LANGER,* CHARLES R. HENDERSON JR.,y and RALPH ORTIZzx

*ZetrOZ, INC, Trumbull, CT, USA; yDepartment of Human Development, Cornell University, Ithaca, NY, USA; zCayugaMedical Center, Ithaca, NY, USA; and xMedical Pain Consultants, Dryden, NY, USA

(Received 13 November 2012; revised 21 February 2013; in final form 5 March 2013)

AQuarry

Abstract—Ultrasound therapy for pain and healing is a versatile treatment modality for musculoskeletal condi-tions that is used daily in rehabilitation clinics around the world. Our group designed and constructed a wearable,battery-operated, low-intensity therapeutic ultrasound (LITUS) device that patients could self-apply and operateduring daily activity for up to 6 h. Thirty patients with chronic trapezius myofascial pain evaluated the LITUSsystem in a double-blind, placebo-controlled, 10-d study under institutional review board approval. Whilecontinuing their prescribed medication regimen, patients with the active device reported on average 1.943 reduc-tion in pain and 1.583 improvement in health relative to placebo devices after 1 h of treatment. Both of these resultswere statistically significant (p, 0.05) for the first 2 d of the study. Male patients reported the majority of benefit,and there is a sex-treatment confound in the sample. The study indicates that wearable, long-duration LITUS tech-nology improves mobile access to drug-free pain relief. (E-mail: george@zetroz.com) � 2013 World Federationfor Ultrasound in Medicine & Biology.

Key Words: Low-intensity therapeutic ultrasound, Wearable ultrasound device, Pain management, Physiotherapy,Clinical study, Outpatient setting, Myofascial pain, Pain management, Therapeutic ultrasound device.

INTRODUCTION

Persistent pain is the principal reason U.S. citizens accessthe health care system according to the National Institutesof Health (2010). Acute as well as chronic pain may seri-ously affect quality of life and is regularly associated withsecondary morbidities such as depression, anxiety andsleep disturbance. Despite increased awareness ofchronic pain and its complications, surveys by the Amer-ican Chronic Pain Association indicate that at least 30%of patients with moderate chronic pain and more than50% of those with severe chronic pain fail to achieveadequate pain relief (‘‘Chronic Pain in America’’ 1999).One pain-causing condition that frequently poses chal-lenges to treatment is chronic trapezius myalgia, whichis associated with repetitive motions of the upper extrem-ities. It is associated with sensitivity and pain in the neckand shoulder areas, and structural changes in the musclefibers of the trapezius have been observed (Larsson et al.1990; Lindman et al. 1991). Current pharmacologic ther-apies are not adequately meeting patient needs, and many

ddress correspondence to: George K. Lewis Jr., ZetrOZ INC, 56Rd, Trumbull, CT 06611, USA. E-mail: george@zetroz.com

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chronic pain sufferers have turned to non-drug therapiesto replace or supplement their use of pharmacotherapies.

Common alternative therapies used to relieve paininclude electrotherapy, traction, braces, the applicationof heat or cold and therapeutic ultrasound. Electrotherapyfunctions through forced stimulation of a nerve, which istargeted to induce a change in the distribution of neuro-transmitters and make it more difficult for a pain signalto propagate (Wright 2012). Its efficacy has been calledinto question, but it is still widely used. Traction is theapplication of mechanical force to relieve pressure onnerves (Mathews et al. 1987). This can relieve pain inthe case where a muscle has been overstimulated or isheld uncomfortably for long periods. Braces functionby providing an alternative means of support for theinjured muscle, reducing the burden on the muscleresponsible for the pain stimulus. The application ofheat or cold is used to stimulate muscle recovery andreduce inflammation, respectively (McCaffery 1990).

Therapeutic ultrasound is often used by cliniciansand physical therapists as a method of relieving painand improving mobility for a variety of musculoskeletalconditions (Belanger 2003; Huang et al. 1999; Loyola-S�anchez et al. 2010, 2012; Pounder and Harrison 2008).Specifically, a number of studies have looked at the effect

Fig. 1. The wearable low-intensity therapeutic ultrasounddevice is approximately the size of a digital music player andprovides a nominal 0.44 W of 2.95-MHz ultrasound for 5 to6 h on a single charge. The device is modeled here as it was

used in this research study on chronic trapezius myalgia.

1430 Ultrasound in Medicine and Biology Volume 39, Number 8, 2013

of short-duration ultrasound on trigger points in the trape-zius of patients whowere myalgic and patients with latenttrigger points (Aguilera et al. 2009; Draper et al. 2010;Esenyel et al. 2000; Majlesi and €Unalan 2004;Sarrafzadeh et al. 2012; Srbely et al. 2008). Trapeziustrigger points are found in the muscle fibers bridgingthe shoulder joint and neck, generally in close proximityto the shoulder-neck angle, which is a point of high strainunder repetitive motion and/or uncomfortable positions(Davies et al. 2004). The formation of trigger points inthis region is believed to result from damaged musclefibers and the opening of the muscle fibers’ sarcoplasmicreticulum, causing the release of calcium and adenosinetriphosphate (ATP) (Kelencz et al. 2011). This leads tolocal uncontrolled muscle contraction and eventual painfrom the trigger point that may present as chronic myo-fascial pain if not treated. The practical benefits of thera-peutic ultrasound treatment in trigger point therapy are itsavailability and non-invasiveness. The clinical effective-ness of therapeutic ultrasound in trigger point therapyfor pain reduction, muscle fiber healing and preventionis still being investigated. A number of theoretical andexperimental explanations exist for the perceived pain re-lief; however, the importance of each proposed pain-relieving mechanism is still undergoing research.Researchers originally hypothesized that the thermaleffects of ultrasound provided the majority of the therapy(Belanger 2003). New research suggests that although thethermal effects are beneficial, there is a second mecha-nism of action caused by the ultrasonic mechanical-tissue interactions (Johns 2002). Studies indicate thatwhen the intensity of the ultrasound treatment is signifi-cantly reduced, thus limiting the thermal effects, andthe length of treatment is significantly increased, thusemphasizing the mechanical effects, beneficial thera-peutic effects are obtained (Cui et al. 2006; Dijkmanet al. 2009; Loyola-S�anchez et al. 2012; Parvizi et al.1999; Pounder and Harrison 2008; Qin et al. 2006). Addi-tionally, the mechanical and thermal mechanisms ofaction in ultrasound have been shown to facilitate woundand bone fracture healing, to promote the penetration oftopical ointments into the skin and to modify biologicalprocesses across a variety of living tissues.

The application of regular extended therapeuticultrasound treatments in health care has been constrainedby technological limits in power transfer, circuit effi-ciency and patient lifestyle. Technology previously estab-lished by the authors has set new thresholds forachievable efficiency with ultrasound and allowed forminiaturization of the ultrasound therapy unit. Our grouphas developed a low-intensity ultrasound device based onultralow impedance design principles, which allows forthe miniaturization and integration of the ultrasoundtransducer, electronics and power supply into a device

that fits easily into the palm of the hand. The 2.95-MHzultrasound system delivers portable, convenient andconsistent long-duration ultrasound therapy. The inte-grated ultrasound system was evaluated in a randomized,double-blinded, placebo-controlled study on chronictrapezius myalgia in 30 patients. Because of the severityof subject pre-medicated pain levels, enrolled patientswere not asked to discontinue their opioid prescriptionmedication regimen to support study compliance. Wetherefore looked at the add-on effect of low-intensitytherapeutic ultrasound (LITUS) in pain management ofthe patients.

METHODS

Overview of self-applied wearable ultrasound systemThe therapeutic ultrasound system is worn on the

shoulder, proximal to the spine (Fig. 1).The therapeutic ultrasound device is a diverging-

wave system that operates at 2.5–3 MHz with 0.03–2W/cm2 ultrasound intensity capability for 0.3–18 h oftreatment depending on the output setting. The systemis based on ultralow electrical impedance and low-voltage design principles and consists of three primaryparts: a 3.7-V lithium-polymer 1500-mA-h rechargeablebattery, a low-output-impedance push-pull radiofre-quency (RF) ultrasound driver with user push-buttoncontrol logic and an ultralow electrical impedance,2.95-MHz divergent ultrasound transducer. The RF elec-tronics are constructed on a printed circuit board andhoused in a polyvinyl chloride plastic enclosure withthe battery pack. The RF ultrasound driver has been

Fig. 2. Electrical impedance spectrum of the wearable low-intensity therapeutic ultrasound transducer. The magnitude isgiven on the left, and the phase is given on the right. Both measured and predicted values are provided in the plot. At

a resonance of 2.95 MHz, the magnitude of the impedance is 3.87 Ohms and the phase is 0 rads.

Wearable self-applied therapeutic US device d G. K. LEWIS JR. et al. 1431

previously described (Lewis and Olbricht 2008a, 2008b,2009). Here we employed a parallel pin-driver configura-tion of four MOSFETs to obtain a non-reactive outputimpedance of approximately 0.5 Ohm and a frequencybandwidth from DC to 40 MHz. The wide voltage andfrequency operating range of the ultrasound drivermade it particularly well suited for portable and low-voltage battery-powered ultrasound applications.

The transducer of the device is housed in a water-proof, biocompatible ring with a polyurethane rubberboot and a 10� ultrasound diverging lens made fromcross-linked polystyrene. The active transducer elementis a lead-zirconate-titanate (PZT-4), silver-plated piezoc-rystal that is air backed. The wide-beam 2.95-MHz ultra-sound was characterized for its electrical impedance and

Fig. 3. Ultrasound beam profiles of wearable ultrasound transdducer. The 10� divergent lens increases the treatment volume of

print versus more traditional collimate

the ultrasound beam shape (Figs. 2 and 3) using themasonmodel (Lewis and Olbricht 2009) and electrical imped-ance spectroscopy (Lewis et al. 2008). The footprint ofthe completed transducer is 28 mm in diameter and4.8 mm in height. The cross-linked polystyrene, ridgedlens along with the high quality factor, Qm, of 1800 ofthe piezo-crystal maintains a ultralow transducer electri-cal impedance of 3.87 Ohms and 0 rads at resonance forlow-voltage power generation with no imaginary losses(Fig. 2) and a divergent treatment volume (Fig. 3).

Under various testing scenarios, the LITUS systemis 70–74% efficient in battery-to-acoustic energy conver-sion. The corresponding transducer efficiency wasmeasured to be 96%, and the RF circuit efficiency wasfound to be 74%. When operated continuously from the

ucer (a) 2 mm and (b) 60 mm from the face of the trans-the transducer over its low-profile 28-mm-diameter foot-d therapeutic ultrasound devices.

Fig. 4. Wearable ultrasound power and system life measure-ment over complete charge cycle. The system lasts 5.5 to 6 hand has a nominal ultrasound power output of 0.44 W over the

entire discharge cycle.

1432 Ultrasound in Medicine and Biology Volume 39, Number 8, 2013

battery at the acoustic 0.44-W nominal output power,which corresponds to a spatial temporal average intensityof 89.6 mW/cm2 at the transducer face, the system lastsbetween 5.5 and 6 h (Fig. 4). For 1- and 6-h treatmentsat this calibration setting, the ultrasound device provides1795 and 9596 J of ultrasonic energy, respectively, calcu-lated by the area under the power curve of Figure 4.Compared the average clinical therapeutic ultrasoundsystems, the wearable ultrasound device is less than1/20th of the size, does not require wall power and mayprovide the same treatment as is customary in currentphysical therapy, that is, short-duration medium-intensitytreatments.

The wearable ultrasound device was supplied ina small kit to each subject in this study. The kit includeda wearable ultrasound device with belt clip, three 2-oz

Fig. 5. Electronic populated printed circuit board of the wear-able ultrasound device pictured between the thumb and pointerfinger. The radiofrequency driver is 15 3 18 mm and employsa parallel MOSFET circuit architecture to maintain low output

impedance for efficient voltage and total energy transfer.

ultrasound coupling gel packets, twenty 10 3 10.5-cmadhesive bandages, a system wall charger, a user manualand a patient diary for self-reporting.

Detailed description of self-applied wearableultrasound system

The wearable ultrasound system was designed fromcommercially available materials to reduce costs. Thefeatures of the system included power control (on/off),biocompatible housing, recharge capability and 5.5 to6 h of ultrasound therapy delivery. The complete ultra-sound devices were calibrated with an ultrasound powermeter (Onda, Sunnyvale, CA, USA) and packaged forthe clinical evaluation.

Electronics. The ultrasound-generating RF circuitdesign previously described (Lewis and Olbricht 2008a,2009) was reduced to a printed circuit board (PCB)(Sunstone Circuits, Mulino, OR, USA) to make theelectronics small, low-cost and reproducible. The 18 315-mm PCB was tested in the laboratory to ensure properperformance and then replicated for the devices used inthis study (Fig. 5). The PCB components consisted ofthe power on/off tactile system controller (Linear Tech-nologies, Milpitas, CA, USA), the megahertz oscillator(NDK, Tokyo, Japan), and two MOSFET push-pulldrivers (Intersil, Milpitas, CA, USA) in parallel. Thepower controller also regulated charging and dischargingof the lithium-polymer battery pack (Battery Space,Richmond, CA, USA). The PCB was designed to behighly efficient, delivering between 90 and 99% of thepower supply voltage directly across the ultrasound trans-ducer, with minimal voltage drop within the MOSFETsbecause of the parallel configuration. Because theultrasound-generating PCB was 15 3 18 mm, multiplecircuits were fabricated on a single wafer.

Transducer. The wide-beam low-impedance trans-ducer consisted of four primary parts: (i) piezoelectric,(ii) polystyrene lens, (iii) air-backed housing and (iv)polyurethane rubber boot for patient comfort and wirestrain relief (Fig. 6). The construction of the ultrasoundtransducer is shown in Figure 6. The 25-mm-diameter,0.7-mm-thick, 3 MHz 6 50 kHz piezoelectric is a modi-fied lead zirconate titanate with electromechanicalcoupling coefficient kp 5 0.58, static capacitance Cs 58600 pF 6 20% at 1 kHz and mechanical quality factorQm 5 1800 (Stiener and Martins, Miami, FL, USA).The full list of material properties of the crystal isprovided in Table 1. The crystal is housed in a 26-mm-diameter polystyrene ring (C-LEC Plastics, Philadelphia,PA, USA), and the front face of the piezo is protected bya 10� polystyrene lens that is secured with cyano-acrylic(Fig. 6c). A low-impedance flexible coax-cable (CoonerWire, Chatsworth, CA, USA) is connected to the

Fig. 6. Construction of the ultralow-impedance low-profile ultrasound transducer. (a) Casting setup for molding therubber boot strain relief shown in (b). (b) Finished rubber boot to cover the active transducer element. (c) Piezo-crystal attached to the polystyrene lens and wired to low-impedance coax-cable. (d) Completed low-profile transducer

used in the wearable ultrasound system.

Wearable self-applied therapeutic US device d G. K. LEWIS JR. et al. 1433

piezoelectric with solder on the inside of the ring housing.The polyurethane rubber boot strain relief was designedfor aesthetics and function using the master shapemachined on a computer-automated milling machine(Sherline, Vista, CA, USA) (Fig. 6a). RTV (room temper-ature vulcanizing) Silicone (McMaster-Carr, Robbins-ville, NJ, USA) was used to make the mold for the bootcasting (Fig. 6a). The rubber boot was made by filling

Table 1. Piezoelectric crystal properties of ultrasoundtransducer

Piezoelectric Material PZT-4 lead-zirconate-titanateDimensions 25 mm in diameter,

0.7 mm thickElectromechnical coupling

coefficientskp 5 0.58kt 5 0.45kt31 5 0.34

Frequency constants (Hz � M) Np 5 2200Nt 5 2070N31 5 1680

Piezoelectric constants(310212 m/V)

d33 5 320d31 5 2140

Piezoelectric constants(31023 V-m/N)

g33 5 2g31 5 211

Elastic constants (31010 N/m2) y33 5 7.3y11 5 8.6

Mechanical quality factor Qm 5 1800Dielectric constant at 1 kHz T33/e0 5 1400Dissipation factor at 1 kHz tan d 5 0.4Curie temperature (�C) Tc 5 320Density (g/cm3) p 5 7.9

the RTV mold with 2056 polyurethane (McMaster-Carr), positioning the mandrel and pin in place in themold and allowing the device to cure (3 h at 50�C)(Fig. 6b). The housing, lens and rubber boot are madeFood and Drug Administration-approved materials forclass 3 medical devices and are not cytotoxic (Fig. 6d).

Electronic and transducer testing. The electronicswere tested over a wide temperature range from 256�Cto 90�C in a dry ice-cooled refrigerator and laboratoryoven. The circuit’s DC voltage and current draw fromthe battery were measured using a digital multimeter(Tektronix, Beaverton, OR, USA). The RF output powerfrom the ultrasound driver to the transducer wasmeasured using a digital oscilloscope (Tektronix),alternating-current (AC) current probe (Tektronix) andvoltage probe (Tektronix) attached to the centerconductor of the coax-cable of the transducer. The root-mean-square (RMS) of the voltage 3 current productwas calculated using the digital oscilloscope real-timeand recorded as the electrical RMS RF output powerinto the transducer. The ultrasound output power wasmeasured with an acoustic power meter with 2-mW reso-lution (Onda). The power meter was calibrated immedi-ately before testing. All measurements were repeatedfive times and used to determine efficiencies of powerconversion. Total system DC-to-acoustic efficiency wascalculated as the ratio of acoustic power out to DC power

Table 2. Performance characteristics of wearableultrasound device

Total acoustic output power 0.44 W 6 10%Average spatial intensity 0.087 W/cm2 6 10%Maximum temporal intensity 0.180 W/cm2 6 10%Frequency 2.95 MHz 6 5%Duty cycle 100%, continuous waveBeam form Diverging, 10� angleApplicator dimensions Circular, 2.5-cm diameter

5-cm2 emitting surface areaBeam non-uniformity ratio ,6:1 (max) 6 10%Effective radiating area 6 cm2

Battery life (max) 5.5 6 0.5 hMaximum treatment duration 6 h

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in. The transducer electrical to acoustic efficiency wascalculated as the ratio of acoustic power out to RF powerin. Circuit efficiency was calculated as the ratio of RFpower out to DC power in. Finally, voltage transfer effi-ciency was calculated as the ratio of voltage across thetransducer during the on drive state to the DC supplyvoltage.

The electrical properties of the ultrasound trans-ducer were mapped using impulse electrical impedancespectroscopy and further refined with 10 specificfrequency impedance measurements around the resonantpoint of the transducer. The electrical impedance magni-tude and phase were fit to the standard Mason model ofa single resonant piezoelectric transducer to determinethe electrical equivalent circuit components and obtainthe transducer’s resonant quality factor.

Final wearable ultrasound system assembly andacoustic calibration. The electronics and battery packwere integrated into a commercially available housing(OKW, Bridgeville, PA, USA). The housing wasmachined appropriately to accommodate the tactile on/off switch, the blue LED on/off indicator light, themicro-barrel recharger port and the coax cable sendingRF energy to the ultrasound transducer. Before finalsystem closure, calibration of the acoustic output powerwas made to be 0.446 0.05 W by adjusting the oscillatorfrequency and inductive matching of the electronic driverto the transducer resonance region. Acoustic power wasmeasured using a calibrated acoustic power meter with2-mW ultrasound power resolution. The LITUS trans-ducer was placed in a power meter filled with degasseddeionized water and rubber absorbing target, the meterwas zeroed and the device was then turned on. The ultra-sound energy from the transducer causes a force that wasdetected on the power meter in acoustic watts. The powermeter is connected to a computer via USB to logmeasurement data from the LITUS device. The spatialaverage acoustic intensity is calculated by dividing thetotal acoustic power by the surface area of the transducer.For the wearable ultrasound transducer with 25-mm

active piezoelectric diameter, the acoustic intensityfrom the device at full charge is 89.6 mW/cm2. Finally,the 10� diverging lens on the devices increases the treat-ment area in addition to natural divergence of the acousticbeam according to r 5 1.251tan(10�) * x, where r 5radius of the circular area being treated in centimeters;and x5 distance from the face of the transducer in centi-meters. The ultrasound intensity as a function of distancefrom the transducer is given by I 5 power/(p * (1.25 1tan(10�) * x)2), where I 5 intensity of the acousticbeam in watts per square centimeter.

Peak spatial and temporal ultrasound intensity ismeasured using a beam scanning system in conjunctionwith a calibrated hydrophone. The beam scanning systemis also used to measure the effective radiating area (ERA)and beam non-uniformity ratio (BNR) and to characterizethe width of the ultrasound acoustic field during develop-ment of the transducer lens. Performance characteristicsof the wearable ultrasound device are summarized inTable 2.

Clinical outcome variablesOutcomes were measured using three clinical read-

outs: visual analogue scale (VAS) score, global ratingof change (GROC) and annotated pain diagrams. VASis a 0 to 10 scale on which patients rate their overallpain level, with 0 representing no pain and 10 represent-ing agonizing pain. It is strictly a reporting of the patient’scurrent pain level. The GROC scale asks patients to recalltheir pain level before treatment, compare it with theirpain level after treatment and give that comparisona numeric score between 27 and 7. Negative numbersindicate an increase in pain and worsening of the condi-tion, whereas positive numbers represent a decrease inpain and beneficial improvement. The annotated paindiagram was completed by the patient before and aftertreatment. It was a diagram of the back, and patientswere instructed to draw circles around areas with minorpain and to mark sites of severe pain. This was quantifiedby comparing the number and severity of the notationsmade by a patient before and after treatment.

PatientsThe research protocol was approved by the institu-

tional review board of Cayuga Medical Center and byPain Management Consultants, and all participants gavewritten informed consent to participate in the study inaccord with the World Medical Association Declarationof Helsinki: Ethical Principles for Medical ResearchInvolving Human Patients. Patients were required (i) tobe between 40 and 60 y of age; (ii) to not be pregnant;(iii) to be willing and able to self-administer treatmentdaily within their place of residence or during normaldaily activity, excluding bathing, showering or other

Fig. 7. Wearable ultrasound device placebo-controlled study protocol and the mean results across 10 d of wearable ultra-sound use on chronic trapezius myalgia. LITUS 5 low-intensity therapeutic ultrasound.

Wearable self-applied therapeutic US device d G. K. LEWIS JR. et al. 1435

water activities that could have resulted in submersion ofthe ultrasound device; and (iv) to undergo an evaluationby a physician to determine if they were functionallyand cognitively capable of self-treatment on a daily basisduring the course of the study; (v) to record any reductionor increase in prescription drug use in their daily diary;and (vi) to be in pain with acute, moderate to severemuscle spasms in the trapezius muscles, as indicated bya VAS pain severity score between 4.0 and 7.0, inclusive,within 4 d before screening. Potential patients wereexcluded if they (i) had known neuropathy; (ii) were preg-nant; (iii) were prisoners; (iv) had had surgery in thetarget area within the last 6 mo; (v) were non-ambulatory; (vi) chose to increase use or initiate newuse of pharmaceuticals during the course of the studyunless medically necessary to ensure patient safety;(vii) used any cream, gel or topical solution during theadministration of treatment other than the approved ultra-sound gel provided at the initiation of the study; (viii) hada clinically significant or unstable medical or psycholog-ical condition that, in the opinion of the physician, wouldcompromise participation in the study; (ix) participated ina clinical trial for an investigational drug and/or agentwithin 30 d before screening; (x) were involved in anyinjury-related litigation in the target area; (xi) had a clin-ically significant abnormal neurologic history or exami-nation at screening (excluding back spasm), includinglumbar radicular symptoms, spinal stenosis, foot drop,herniated nucleus pulposus or other structural defects;or (xii) had back spasm related to major trauma ora work-related injury, or had other severe pain that may

have confounded assessment or self-evaluation of thetrapezius myalgia.

Thirty patients who met the sampling criteria wererecruited for the study. They were randomly assigned tothe placebo (10 patients) and active (20 patients) condi-tions. Patients were recruited sequentially and assignedas recruited on a 2:1 basis to active and placebo. Bychance in the sampling, there were 10 males and10 females in the active group but a disproportionate 1male and 9 females in the placebo group. Both the clinicstaff and the patients were blind to their treatmentassignment.

The 30 patients participated in at least ten 1-h ultra-sound treatment sessions at the onset of heightened paincaused by trapezius spasm. Each treatment session wasself-diagnosed, the ultrasound therapy was self-appliedand VAS/GROCmetrics were self-reported in a user dailydiary. All 30 patients completed at least 10 treatmentsessions with 100% compliance and no patient dropout.One study kit was accidently broken by a subject; thisdevice was replaced with an identical device withoutthe patient or clinical investigator knowing whether thedevice was active or a placebo. Once trained by researchassistants, patients were able to self-apply the ultrasoundtreatment in their own homes and/or work environmentsin most treatment cases.

Handling of devices and dataAll devices and kits were tracked by serial numbers

and have an associated log with key to placebo-sham andactive device. Each device log tracked any repairs,

Fig. 8. Daily visual analogue scale (VAS) percentage reductionin pain, with standard deviation error bars, from the start tothe end of a 1-h ultrasound treatment. Across the 10 treatmentsessions, the average pain reduction is double that observedwith a placebo, primarily because of the males in the

active group.

1436 Ultrasound in Medicine and Biology Volume 39, Number 8, 2013

defects, issues, returns or other activities associated withthe unit. The key was provided to the statistician (C.R.H.)but was kept blinded from the research assistants and theclinical investigator (R.O) enrolling patients and issuingkits. Data from each daily diary were tabulated by theresearch assistants and provided to C.R.H. for statisticalanalysis.

Statistical models and methodsThe core statistical model includes fixed classifica-

tion factors for treatment assignment and time of assess-ment; age as a covariate; and patients as levels ofa random classification factor. We initially examineda two-level treatment variable (placebo vs. active);because of the imbalance of sex of subject in the placebogroup, it was not possible to include sex, treatment, andtheir interaction in the model, and in final models we

Fig. 9. Improvement in global rating of change (GROC) scoreafter low-intensity therapeutic ultrasound therapy. Across the10 treatments, the average improvement in the test group was

1.6 times that observed with a placebo.

used a three-level variable: placebo, active females andactive males. The tests of treatment effects are the testsof the interaction of treatment and time and 23 2 subsetspartitioned from this interaction. Analysis was by generallinear mixed models with an assumption of an unstruc-tured error.

Visual analogue scale. There are five pain reports oneach of 10 d for each subject. We examined models withtwo repeated-measures factors, day of assessment (10)and time of assessment in a given day (5), and modelswith the single repeated measure for day of assessmentand various functions of the daily scores as the dependentvariable (e.g., the difference score between the fourth andfirst VAS measurements). For reporting results in thisarticle, the dependent variable in the model witha repeated measure for day is the fourth assessment minusthe first assessment (the quantity) divided by the firstassessment. This is equivalent to the fourth divided bythe first, but is in the more natural form. In this model,we specified a priori a contrast for levels of the treatmentfactor restricted to the first 2 d. We also examined time asa covariate in a growth curve model.

Global rating of change. The daily scores over thefirst 10 d were the outcomes in a repeated-measuresmodel of the type described for VAS.

Pain Diagram. If a patient did not indicate whichwas the focal shoulder and on which shoulder the devicewas worn, we used the average of the reports for bothshoulders. With this outcome, the model is the same asfor GROC and VAS.

Results were considered significant with a p-value#0.05; p-values .0.05 and #0.10 are discussed astrends.

RESULTS

Patients successfully recorded their pain and overalltherapeutic benefit scores using the visual analogue andglobal rate of change scales, respectively. Patients alsosuccessfully annotated a pain diagram of the upper backpost-LITUS treatment. Figure 7 shows the average painreduction for these three primary outcomes averagedover the 10 d of treatment.

The VAS results among all patients were positive,with the majority of patients reporting the greatest reduc-tion in pain during the first 3 to 4 d of usage (Fig. 8). Onaverage, placebo users had an 8% pain reduction, femaleactive users had a 12% pain reduction, and male activeusers had a 19% pain reduction (Fig. 7). The 2 activegroups differed significantly from placebo over the first2 d (p5 0.03) (Fig. 8). This was duemore to activemales,who differed significantly from placebo (p5 0.04); activefemales differed from placebo as a trend (p 5 0.10).

Wearable self-applied therapeutic US device d G. K. LEWIS JR. et al. 1437

Across the 10 treatments, the average GROC scorein the test group reported improvement 60% greaterthan that reported in the placebo group. Placebousers had a 0.36 GROC improvement, female active usershad a 0.41 GROC improvement and male active users hada 0.73 GROC improvement (Fig. 7). Over the first 2 d, theactive group differed significantly from placebo (p 50.05), with active males significantly different fromplacebo (p 5 0.05) and producing the overall difference(Fig. 9).

The average reported upper back pain after 60 minof LITUS treatment on days 1 through 10 using the anno-tated patient diagram was recorded by all trial patients(Fig. 10). Female patients receiving ultrasound treatmentreported no statistically significant or trending effectsversus placebo. On average across the 10 treatmentsessions, active female patients reported slightly higherpain than placebo control. Across the entire 10 d, activemen reported a 30% reduction in pain over placebo,a significant difference (p 5 0.02) (also significant forthe first 2 d, p 5 0.004).

Figure 11 illustrates the temporal percentage changein VAS over a 60-min treatment and 60-min post-treatment as recorded in the patient’s diary averagedacross the 10 treatment sessions. Active male and femaleusers respond faster than placebo treatment as shown bythe greater slope in the percentage pain reduction graphs.The mean time to pain reduction (MTPR) is calculatedfrom Figure 11 using the placebo 60-min time point 8%VAS reduction as the nominal comparative value. Toreach this respective pain reduction value, female activeusers had a MTPR of 29 min, whereas male active usersreported a 13-min MTPR. This corresponds to improve-ments of 52% and 78%, respectively, over placebo.

Fig. 10. Overall pain in upper back after 1 h of low-intensitytherapeutic ultrasound treatment, with standard deviationerror bars. Active male patients across the entire 10 treatmentsreported 30% lower pain than with placebo (p 5 0.02). Activefemale patients had results similar to those of the placebo

treatment group.

Post-60-min LITUS treatment, placebo and active malegroups reported increased pain as shown at the 120-minmark in Figure 11, whereas active females reporteda continued decrease in pain after conclusion of the60-min treatment.

DISCUSSION

Our group has revealed the feasibility and safety ofchronic muscle pain relief with a self-delivered, wear-able, therapeutic ultrasound device in an opioid-medicated population of chronic pain sufferers. Thedevice itself is smaller than a typical smart phone andwas not reported to interfere with patients’ normalactivity patterns during the study. Overall, the wearableLITUS device provided a means for pain reduction andhealth improvement over placebo in this small clinicaltrial carried out in a disparate population of rural patientsat a regional pain clinic in central New York State. Allpatients involved in the study were able to self-applyultrasound therapy successfully in their own homes andduring daily activity after a short 20-min training session,and no adverse events were reported during or after thestudy.

This study is distinct from other studies of thera-peutic ultrasound treatment of the trapezius. In otherstudies, a higher intensity (.1 W/cm2) was employed,and the duration of the treatment was on the order ofminutes (Aguilera et al. 2009; Draper et al. 2010;Sarrafzadeh et al. 2012; Srbely et al. 2008). Additionally,the other studies in the field have looked at the painthreshold caused by either compression or stretching.This study allowed testing of the benefit of ultrasoundtherapy on normal activity and reporting on the ability

Fig. 11. Temporal average percentage reduction in visualanalogue scale during and after low-intensity therapeutic ultra-sound therapy across 10 treatment sessions. Active female andmale users reported 52% and 78% more rapid MTPR compared

with placebo treatment group.

1438 Ultrasound in Medicine and Biology Volume 39, Number 8, 2013

of the treatment to reduce pain during lifestyle use, whichare of more direct clinical relevance than previous datacollected. Finally, the patients who were evaluated inthis trial were already on opioids and other pain medica-tions and were not asked to cease or change their medica-tion regimen. So the statistically significant benefitsobservedwith the ultrasound treatment are in a populationthat is already pain controlled.

In this 30-patient placebo-controlled double-blindedstudy, active users of the device reported an average painreduction double that reported with a placebo and animprovement in global health 60% larger than that at-tained with placebo. In this study, active male patientsclearly had larger pain reductions and overall improve-ments n response to the therapeutic device than did activefemales. The evaluation of the effect of the device islimited by the lack of males in the placebo group. Thisconfound makes it difficult to determine whether differ-ences between active males and placebo are treatmenteffects or sex effects. We did, however, observe globalhealth improvements on a day-to-day basis in the treat-ment group.

CONCLUSIONS

Our group believes that these are both significantand successful early clinical results, particularly becausethe patients involved in this study maintained their painmanagement medication regimen during the evaluationof the LITUS system. Furthermore, the results of thisstudy and the means and variances of visual analoguescale, global rating of change and annotated pain scoressupport a larger clinical study by the investigative team.Thewearable ultrasound system proved useful as an adju-vant therapeutic approach to reducing patients’ chronictrapezius myalgia while producing no reports of negativeside effects.

Acknowledgments—The authors thank the CayugaMedical Center insti-tutional review board for reviewing and overseeing human subjectparticipation in this study. The authors thank Professor M. CarringtonReid of Weill Cornell Medical College for guidance on this researchand interpretation of results. The authors also thank Transducer Engi-neering Inc. for transducer fabrication support. Finally, the authors thankthe Center for the Integration Medicine and Innovative Technology (CI-MIT) for supporting this research.

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